Executive Secretary Hany Demiancalled the meeting to order at 9:32 a.m. He noted that Albert
Aboulafia, M.D., John Doull, Ph.D., and Andrew Schmidt, M.D., had been
appointed to temporary voting status. Mr. Demian then read the conflict of
interest statement. Albert Aboulafia, M.D., John Kirkpatrick, M.D., Kinley
Larntz, Ph.D., and Andrew Schmidt, M.D., had been granted waivers for their
interests in firms that could be affected by the panel’s recommendations; they
could participate fully in the panel’s deliberations. The Agency took into
consideration other matters regarding Maureen Finnegan, M.D., John Kirkpatrick,
M.D., Karen Rue, Andrew Schmidt, M.D., and Michael Yaszemski, M.D., Ph.D., who
reported interests in firms at issue but in matters not related to the day’s
agenda; they could participate fully in the panel’s deliberations. Mr. Demian
then asked the panel members to introduce themselves.

Panel
Chair Michael Yaszemski, M.D., Ph.D., introduced himself and stated that
the purpose of the meeting was to make recommendations on a PMA for a growth factor
soaked in collagen sponge to treat tibial fractures. He noted that the panel
members present constitute a quorum.

OPEN PUBLIC HEARING

No comments were made.

SPONSOR PRESENTATION

Owen Fields, Ph.D.,worldwide
regulatory affairs, Wyeth Research, described InductOs, a combination
product consisting of an absorbable collagen sponge (ACS) soaked with
recombinant human bone morphogenetic protein-2 (rhBMP-2), an osteoinductive
protein. The sponge is manufactured by Integra Life Sciences and is also marketed
as the Helistat sponge; rhBMP-2 is produced by Wyeth. Only the 1.5 mg/mL dosage
of rhBMP-2 is proposed for marketing.

The preclinical
research involved both device and drug studies. The combination product is
biochemically identical for all uses. Because the FDA approved the INFUSE spine
fusion product in July 2002 and information on the manufacture of rhBMP-2 and
ACS has therefore already been provided to the panel, Dr. Fields did not focus
on the preclinical safety program.

Rod
Riedel, Ph.D., project management, Wyeth, summarized preclinical studies
demonstrating bone induction in animals. Bone induction is unique to rhBMP-2.
The ability of the protein to induce bone growth de novo provides the rationale
for replacing standard therapy components (e.g., bone graft) or augmenting
standard therapy. Preclinical safety findings found that no toxicity or
systemic effects occurred; the drug is eliminated rapidly, and low systemic
exposure occurs. The preclinical research both in animal models and in vitro demonstrates
that the protein accelerates healing and establishes the safety profile of the
device. The research supports the clinical use of InductOs in fracture
treatment.

Alex
Valentin, M.D., senior director, clinical R&D, Wyeth, presented results
of the pivotal clinical study, which was a prospective, randomized, multicenter
study involving 450 patients with open tibia fractures, 300 of whom were
treated with the device. Dr. Valentin presented information on the study
rationale, design, patient characteristics, results, and conclusions. He noted
that open fractures involve the tibia more often than any other bone.

The
pivotal study was single blind and designed to use stratified randomization;
patients were not aware of which treatment group they were in. Both the
treating physician and an independent radiological panel assessed outcomes
using the same x-ray films. Union was defined as at least three or four
cortices being breached on two or more views. Patients were followed for 12
months in 7 visits. Patients receiving prophylactic bone grafting were excluded
because the treatment is rarely prescribed; therefore, should the product be
approved, patients requiring prophylactic bone grafting should be excluded.
Investigators could use reamed or unreamed nails because there is no
international consensus on which nails work best. Patients randomized to the experimental group received standard
care plus the device in either an 0.75 mg/mL or a 1.5 mg/mL dose. The study
demonstrated the superiority of the 1.5 mg/mL dose compared with the control
group.

Dr.
Valentin noted that the study is as standardized as possible given the nature
of orthopedic trauma. No consensus exists on the definition of delayed union or
healing; for the study, assessment of delayed union and healing was based on
the prospective collection of signs and symptoms supporting the investigators’
assessment.

Dr.
Valentin described the patient demographics and fracture characteristics and
stated that the similarities across groups were sufficient to permit pooling
the data. Patients tended to be white men in their early 30s; nearly two-thirds
of the patients had been involved in motor vehicle accidents, and about half
were smokers. Compared with the control group, patients in the 1.5 mg/mL
experimental group experienced significantly less treatment failure and fewer
interventions. Significantly more patients in the 1.5 mg/mL group experienced
healing by 26 weeks without secondary intervention to promote healing, as
assessed by the investigator. In addition, patients in the 1.5 mg/mL group
experienced accelerated fracture union at 26 weeks, as assessed by the
radiology panel.

In
response to FDA concerns that the study subjects were too heterogeneous, Dr.
Valentin stated that no one category influenced study results and that the
homogenous efficacy results justify pooling the data. Although FDA had
expressed concern that the assessments of outcomes were biased, investigator
assessments of treatment success or failure were corroborated by patient
symptoms, reintervention decisions were made at comparable timepoints across
treatment groups, and healed patients did not regress.

Even though the
patients in the study experienced comparatively high incidence of infections,
the rate was comparable across the three groups and was most common in the
patients with the most severe fractures, suggesting that rhBMP-2 did not
increase the likelihood of infection. Hardware failures were more likely in the
control and low-dose groups and were most common for patients receiving
unreamed nails. No ectopic calcifications were found to be due to rhBMP-2. The
incidence of heterotopic calcifications was low, although patients receiving
the InductOs device experienced a slightly higher, not statistically significant
rate. In addition, antibodies to rhBMP-2 were found in a small number of
patients.

Marc
Swiontkowski, M.D., University of Minnesota Medical School, Minneapolis,
presented information on the clinical relevance of the study findings to the
U.S. trauma population. Open tibia fractures are associated with a high rate of
delayed union requiring secondary procedures. The results of the study are
applicable to other, less severe fractures. He pointed out that the pivotal
study had a measurable endpoint, was clinically meaningful, and was consistent
with other trials. The study was conducted using the highest quality design
available and demonstrated that the InductOs device is safe and accelerates
healing in long bones.

FDA PRESENTATION

Aric Kaiser, M.S., PMA lead
panel reviewer, described the device, reviewed the indications for use, and
presented the submission history of the device. He noted that this is the
sponsor’s second submission; the sponsor has submitted a reanalysis of the
original data to address earlier deficiencies. FDA is reviewing only the tibia
data presented as a result of the clinical trial. Some outstanding preclinical
issues include the effects of rhBMP-2 on tumor promotion and fetal development.

Barbara
Buch, M.D., CDRH, presented FDA’s clinical review. She noted several issues
concerning the clinical study that related to confounding variables, patient
assessment, endpoints, and data analysis. Many variables affect fracture
healing, the most striking of which is the nail insertion technique.
Statistically significant differences were found between the control group and
the experimental groups. Patients in the experimental groups were more likely
to receive reamed nails; the difference may be clinically significant. Also,
the group receiving the larger dose of rhBMP-2 had a slightly higher proportion
of large-diameter, unlocked nails. Fracture types were considered collectively,
rather than by fracture type; however, different types of fractures were dealt
with differently. Also, the protocol allowed for less than a full sponge to be
inserted, so not all patients received same dose; it is unclear how that might
have affected the rate of healing. Although no statistically significant
differences were found between large and small centers, they handle fractures
differently and have different experience levels. Diverse cultural expectations
existed across sites. Half the patients were enrolled in two countries (South
Africa and Germany), and several sites had fewer than 10 patients. Patient characteristics
differed from country to country, and the types of fractures treated in each
country differed. The ability to extrapolate to U.S. populations was not
clearly demonstrated.

Dr.
Buch also listed various problems with the clinical assessment methods. No
standardized assessment methods were implemented. The criteria for radiographic
union for independent radiology panel are problematic. A definition of healed
fracture was set forth, but it was not clear whether all three of the
definition’s criteria had to be met. The difference between delayed union and
delayed healing is unclear. Also, it is not clear how the decision to undertake
secondary intervention was made. Finally, use of prophylactic bone graft may be
helpful, but the sponsor excluded those patients. Although treatment groups
received a substance to enhance bone healing, the control group did not—so was
the control group treated comparably?

The
primary endpoint had four subgroups, but a combined clinical and radiological
endpoint (CCRE) was used, an analytical method that has not been validated. The
CCRE was composed of subjective assessment plus objective assessment—that is,
two dissimilar assessments, rather than two radiological assessments. Patients
with secondary interventions were treated differently; they were paired with
the results of independent radiology review at the time the decision to
intervene was made. Treatment of missing data was inconsistent.

With
regard to effectiveness, Dr. Buch noted that 6 months may not have been an appropriate
endpoint because the differences between the investigators’ and the radiology
panel’s assessments were so marked. The experimental and control groups showed
little difference in time to fracture healing, as determined by the independent
radiology panel.

Concerning
safety, Dr. Buch pointed out that the rates of authentic antibody responses are
higher than in other studies of this type of device. Twelve patients (6
percent) had an authentic immune response. The contribution of the trauma
setting to the response and its clinical significance is not known. Liver and
pancreas function tests showed higher levels of amylase and higher rates of
hypomagnesemia in the experimental group than in the control group, findings of
concern because a patient in a previous study of rhBMP-2 was diagnosed with
pancreatic cancer. Infection rates seem a bit higher than in other studies.

Chang
S. Lao, Ph.D., Division of Biostatistics, OSB, presented the FDA
statistical review. One problem is the poolability of the data due to the
heterogeneity among the centers; the sponsor’s approach to analyzing the data
is not valid. Survival analysis is required because patients were censored or
lost to follow up. In addition, it is not clear that the study could be
reproduced because so many subjective judgments were used in determining
patient outcomes.

PANEL DISCUSSION

Sanjiv Naidu, M.D.,
summarized the preclinical results. He described several studies using animal
models and concluded that not all the studies demonstrated the effectiveness of
rhBMP-2 to promote fracture healing. The results are equivocal. His “gut
feeling,” however, is that the protein does enhance bone formation, but its
clinical usefulness will be hard to demonstrate.

Maureen
Finnegan, M.D., presented the panel’s clinical review. She reviewed the
problems with the pivotal study design. Many patients received rods at first
intervention, which is not the standard of care in the United States. Why did
several very capable countries contribute only a few patients to the study? Was
the study protocol not the standard of care in those countries? Did the centers
see few open tibial fractures? If so, she would be concerned about their
experience. She highlighted several differences between the control group and
the experimental group (e.g., the control group had a larger number of unreamed
nails and more patients with multiple fractures). Dr. Finnegan noted that the
sponsor stated that the ACS needs to touch both ends of the fracture, which
suggests that osteoconduction is the primary method of fracture healing. CCRE
has no validation associated with it.

The
biggest concern is that BMP antibodies were found among patients in the
experimental group. No one understands what this finding means. The safety and
efficacy of repeat use of the device are unknown. In sum, one cannot conclude
anything from the pivotal study. The product shows borderline efficacy, but it
seems safe. All we know is that the material does not interfere with healing.

Kinley Larntz,
Ph.D., provided the panel statistical review. He stated that the sponsor’s
study does show an effect of rhBMP-2. Nevertheless, there is a question about
the poolability of the data. In the statistical analysis, one must take into
account random effects. If one conducts the analysis using a logit scale, which
the sponsors tried to do, one would find insufficient data to conduct the
analysis. Dr. Larntz would use a Bayesian analysis, which would reveal a
significant effect of rhBMP-2 with respect to the number of reinterventions.

An
important aspect of the sponsor’s study is the censoring of data. The censoring
with respect to radiological assessment or investigator assessment was
considerable. For example, in radiological assessment, the rate of censoring at
150 days was 37 percent for the control group, meaning that there were no data
for radiological assessment for 37 percent of those patients after 150 days.
For the group receiving 1.5 mg/mL doses of rhBMP-2, the rate was 16 percent.
The differences in censoring rates between the groups is of concern. If we make
adjustments for censoring, there is no difference between the three groups in
terms of radiological assessment. If you adjust for the differences between
reamed and unreamed nails, it reduces the effect of the 1.5 mg/mL dose on
secondary interventions.

OPEN PUBLIC HEARING

Bill Christianson, Orthopedic
Surgical Manufacturer’s Association, urged the panel to focus on the safety and
effectiveness of InductOs. He reviewed the meanings of “safe” and “effective”
and noted that the regulations and the law clearly state that the standard is
“reasonable.” The standard is not proof beyond shadow of doubt.

Question
1: Discuss the adequacy of data from
experience treating acute open tibia fractures stabilized with IM nails to
support a more general indication.

The panel generally agreed with the
sponsor that the indication should cover long-bone fractures in general, not
just tibia fractures. However, panel members noted that the data may or may not
support use in open tibia fractures and that it may be problematic to
extrapolate to other fractures. More data are needed.

Question 2: Discuss the impact of the
following on the ability of the study to collect clinically valid data: (1)
definition of standard of care in view of the multiple confounding factors; (2)
clinical relevance of the rate of secondary interventions required to promote
healing as a primary endpoint; and (3) reliability of interpretation of terms
“union,” “healing,” “delayed union,” and “delayed healing” at various sites.

The panel concurred that the
standard of care was acceptable with some caveats: The local standard of care
may have affected the choice of nail, and other differences may have affected
the infection rate. In a global sense, however, the standard of care was met.
Other noninvasive means may have been appropriate additions. Also, because some
patients did not get the full sponge, there was variation in the rhBMP-2 dose
received. The panel also concurred that the study had flaws in the definitions
of union and healing and that the investigators demonstrated enthusiasm for
study material.

Question 3: Accounting for trial design, resulting
data, and statistical analyses, discuss the adequacy of effectiveness in terms
of (1) the decrease in number of secondary interventions required to promote
fracture healing and (2) accelerated fracture healing determined by fracture
healing at 6 months assessed by investigator and fracture union assessed by
independent radiologist.

The panel concurred that the device is generally effective,
but the study data are equivocal.

Question
4: Accounting for trial design and
resulting data, discuss whether or not the sponsor has provided a reasonable
assurance of device safety in view of the rate of authentic antibody response
to rhBMP-2 and to bovine Type I collagen, rate of hardware failure, rate of
infection, and rate of abnormal liver function for lab values.

The panel agreed that the rate of
hardware failure and infections is not a major concern. Several panel members
commented on the nature of the antibody response—it may warrant looking at
patients over time. Trauma may have an effect. Also, panel members expressed
concern about the relation of the antibody response to tumors. The panel
generally concurred that the device is safe.

OPEN PUBLIC HEARING

No comments were made

VOTE

Mr. Demian read the voting
instructions. The panel voted 6-1 to approve the PMA with the following
conditions:

Use of
the device should be limited to penetrating fractures that, in the opinion
of the treating surgeon, represent fractures that would benefit from
device.

Users
should be educated about the device.

The
labeling should state that the effects of repeated use are unknown with
respect to antibodies.

Two
studies on antibodies should be conducted—a natural history study and an
animal or human study.

Postmarket
surveillance should be conducted to clarify the issue of accelerated
fracture healing.

The
sponsor and FDA should work out the statistics concerning the presence of
fibula fracture fixation and its effect on endpoints.

When asked to explain the reasons
for their votes, panel members responded that the device is safe, but its
effectiveness is only weakly demonstrated, if at all. Many felt that the
sponsor could produce a better study. The panel member voting not to approve
the device did so because the preclinical data were mixed, the clinical data
had too many confounders, and the x-ray data were not complete; the healing
criteria were varied.

GENERAL DISCUSSION ON SPINAL DEVICES

OPEN PUBLIC HEARING

Dr. Brenda Seidman, Seidman
Toxicology Services, said that FDA’s proposal to require in vivo particle
injection studies for spine devices is problematic. She raised numerous
questions concerning the appropriateness of such a requirement.

Diane
Johnson, vice president, Regulatory Affairs, Spinal Dynamics Corporation,
requested that the panel consider FDA’s position on durability testing and its
relationship to wear-particle testing. She asked the panel to consider whether simulation
testing for disc devices should reflect activities of daily living or maximum
loads and motions, as sometimes suggested by FDA. She also asked the panel to
consider whether particle size distribution and quantity should be determined
using a load and motion profile associated with activities of daily living.
Finally, she asked whether the generation of particulate due to nonphysiologic
loading necessarily invalidates animal models in terms of evaluation of the
effects of particulate that is generated in the animal.

Bailey
Lipscomb, Ph.D., vice president, clinical affairs, Medtronic Sofamor Danek, raised
several issues. First, in clinical trials, Oswestry pain success should be
based on improvement from baseline, with a goal of 20 percent improvement.
Second, neurological status is just one component of success; fusion, pain, and
device criteria also are important. Currently, anything affecting neurological
success affects the total success rate for studies. A person could have reduced
pain and many sensorimotor improvements, but if one neurological criterion is
reduced, it is counted as failure. The standard is inappropriate. Third, FDA is
requiring unnecessarily large clinical study sizes.

Richard Jansen,
Pharm.D., vice president, regulatory and clinical affairs, Disc Dynamics, Inc.,
raised three issues. First, in clinical studies, the radiographic endpoint
of motion on flexion and extension films should be a secondary endpoint; the
main endpoint should be clinical. Patients will consider surgery successful if
they have reduced pain and a return to activities of daily living. Second, the
baboon model is inappropriate for disc nucleus prostheses. The disc base is too
narrow, and the nucleus cavity is too small. Third, spine arthroplasty devices
should not be required to last the life of the patient. Each type of device
must be considered individually.

Britt
Norton, Raymedica, Inc., Bloomington, MN, spoke about preclinical testing
related to nonfusion spinal devices. The tests used to evaluate prosthetic
nucleus devices must recognize the fundamental differences between those
devices and fusion devices in order to provide meaningful results. It is
important to differentiate between tests that characterize the materials used
in a device and tests that evaluate the intended function of the device. He
raised issues concerning tests for compression fatigue, durability, and shear
testing; migration and expulsion; creep and stress relaxation; and potential
for generating wear debris.

FDA PRESENTATION

Dr. Buch presented background on
the guidance document for preparation of IDEs for spinal systems. She stressed
that the panel discussion is not related to approval of a specific device. The
current spinal guidance focuses on fusion devices, and it needs to be updated
to incorporate new devices.

Panel Reviews

John S. Kirkpatrick, M.D., provided
the panel preclinical and clinical reviews. He noted that the panel is being
asked to recommend tests for unknown devices even though there are no validated
test methods. The panel will ask for companies to satisfy the burden of safety
and effectiveness. The extensive nature of the tests are high, but compromise
is required.

Devices
should be tested in all anticipated loads and motions. Physiologic load needs
to be considered seriously. In addition, mechanical characteristics should
include device changes after testing for durability, wear, debris, plastic
deformation, and other changes. Migration and expulsion tests are important, as
are tests for static and dynamic shear testing, creep, and stress relaxation.
Evaluation of bone–implant interface may be important. For devices intended to
preserve motion, the limits need to be defined; stability testing is the way to
get at that. Failure at the extremes of motion must be characterized.
Biocompatibility and toxicity testing for new materials and characterization of
corrosion, wear, response to debris, and shelf life all are important. The
effects of debris on the spine are unknown, and animal models provide us with
the best guess at present. Radiographic measures are challenging at best.
Investigators should consider making indications as refined and specific as
possible.

Concerning
safety, sponsors should consider the revision options after device failure. Is
replacement an option, or is fusion the only option? All neurological effects
should be reported. In summary, nonfusion
devices will generally require more extensive evaluations, longer in vitro
testing, and longer clinical followup. FDA should set forth exhaustive guidance
and adjust requirements to specific device applications if a sponsor provides
an appropriate rationale.

John
Doull, Ph.D., provided the panel safety review. Safety boils down to
whether a device has a toxic effect or a physiologic effect. Dose affects
toxicity. Much is known about silicone, asbestos, and solid-state
tumorigenesis. As one reduces the size of the particle, one reduces the
propensity of the material to induce tumor. The kind of neurological testing
one might do to look for particle-size effects does not have any good animal
models. Good models are needed.

Question 1: Please comment on the currently
recommended preclinical mechanical, debris, or wear testing to evaluate new
materials, device properties/integrity and wear debris for fusion and
non-fusion devices. Discuss what additional testing, if any, should be added to
current testing recommendations for the following devices: stabilization
devices for non-fusion; intervertebral disc/joint replacements
(cervical/thoracolumbar); devices manufactured out of new materials; and
intervertebral disc nucleus replacements.

The panel concurred that the
guidance adequately specifies the necessary tests. The problem is that
nonfusion devices come in many types of materials and polymers. Viscoelastic
testing is required, and there are many types of tests. Because the materials
are so variable, these issues should be addressed individually with the device
sponsors.

Question
2: Because of the limitations of the
current testing methods and models, should devices made of new materials and/or
those intended to retain motion be tested for neurotoxicity independent of the
type of material or the amount of wear debris generated? If you suggest that
testing be performed, please describe the testing you recommend.

The panel concurred that
wear-debris testing is important. Members proposed various types of testing,
such as placing particulates in the area of intended use adjacent to the dura
and testing in conventional modes. Physiologic loading to represent the most
vigorous patient type, instead of maximal loading, would be appropriate. The
panel concurred that it is important to place a barrage of particles at the
site of implantation and study the reaction. Panel members noted that the
manufacturer should not be required to produce particles of a size not produced
under wear conditions and that FDA needs to be careful not to put too high a
burden on manufacturers.

Question 3a: Please
discuss study designs which may be better suited to evaluate Non-Fusion spinal
devices. In your discussion, please comment on enrollment criteria, patient
populations, controls, success criteria and goals of the study that would be
suitable for these types of non-fusion spinal devices.

The panel concurred that it is
important to look at the natural history of nonfusion devices; the devices may
affect degenerative changes at adjacent segments. Investigators need to
carefully consider specific indications for each device. Success should include
improvement of pain and functional capacity. Patient success is multivariate
construct.

Question 3b:
Devices intended to stabilize the spine yet retain functional motion are
expected to have an upper limit of motion beyond which one would consider the
device to be unstable and a lower limit below which one would consider the
device to have inadequate motion or possibly even consider the segment to be
fused. Please discuss the amount of motion and on what scale, to define a
patient as a functional and clinical success (i.e., a clinically significant
improvement in condition) for each of cervical, thoracic and lumbar levels for
Non-Fusion spinal devices.

The panel concurred that it was not
useful to require an arbitrary level of motion. If a patient receives a
nonfusion device and improves, then the device is efficacious. The panel
concurred that is important to study a wide range of diagnoses; indications for
replacement versus fusion are important factors in product design.
Investigators must determine whether interventions would affect adjacent
deterioration. Success criteria should include pain level as well as range of
motion.

ADJOURNMENT

Mr. Demian thanked the participants and adjourned the panel
at 4:22 p.m.

I certify that I attended this
meeting of the Orthopaedics and Rehabilitation Devices Advisory Panel on
November 21, 2002, and that these minutes accurately reflect what transpired.